N-methyl-2-pyrrolidone → (E)-4-(dimethylamino)-N-methyl-N-(6-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide

HRID 404794Notes

Reaction equation

HRID 404794 reaction equation
Cl.[CH3:2]N(/C(=C\C)/C(O)=O)C.C(Cl)(=O)C(Cl)=O.[CH3:17][NH:18][C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:35][CH:34]=3)[N:29]=[CH:28][N:27]=2)[CH:22]=[CH:21][CH:20]=1.[CH3:46][N:47]1[C:51](=[O:52])[CH2:50][CH2:49][CH2:48]1>CC#N.CN(C=O)C.CCOC(C)=O>[CH3:2][N:47]([CH3:46])[CH2:48]/[CH:49]=[CH:50]/[C:51]([N:18]([CH3:17])[C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([NH:25][C:26]2[CH:31]=[C:30]([NH:32][C:33]3[CH:38]=[CH:37][C:36]([O:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:35][CH:34]=3)[N:29]=[CH:28][N:27]=2)[N:24]=1)=[O:52]

Participants

8

Reactant 4

HCID 13387N-methyl-2-pyrrolidoneHCID 65578Oxalyl chlorideHCID 57708271N4-(6-(methylamino)pyridine-2-yl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamineHCID 86630629Dimethylaminocrotonic acid hydrochloride

Product 1

HCID 42601658(E)-4-(dimethylamino)-N-methyl-N-(6-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideCatalystHCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent

Procedure

To a solution of dimethylaminocrotonic acid hydrochloride (0.120 g, 0.72 mmol) in CH3CN (1.4 mL) was added DMF (1 drop) followed by oxalyl chloride (0.07 mL, 0.91 mmol) at 0° C. under nitrogen atmosphere. The reaction was allowed to stir at this temperature for 30 min and then at rt for 2 h. This acid chloride was added, drop wise, at 0° C. in to a stirred solution of N4-(6-(methylamino)pyridine-2-yl)-N6-(4-phenoxyphenyl)pyrimidine-4,6-diamine (0.07 g, 0.18 mmol) in NMP (2.8 mL). The reaction was allowed to stir at 0° C. for 1 h, diluted with EtOAc (5 mL), and washed with 10% NaHCO3 (2 mL), water (2 mL) and brine (2 mL). drying over Na2SO4 followed by concentration under reduced pressure gave a residue which was further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1) to give (E)-4-(dimethylamino)-N-methyl-N-(6-(6-(4-phenoxyphenylamino)pyrimidin-4-ylamino)pyridine-2-yl)but-2-enamide (I-79) as a yellow solid. 1H NMR (DMSO-d6) δ ppm: 2.05 (s, 6H), 2.91 (d, J=6 Hz, 2H), 3.27 (s, 3H), 6.08 (d, J=15.2 Hz, 1H), 6.65 (dd, J=5.6 & 14.8 Hz, 1H), 6.82 (d, J=7.6 Hz, 1H), 6.97-7.00 (m, 4H), 7.10 (t, J=7.2 Hz, 1H), 7.20 (s, 1H), 7.35-7.39 (m, 2H), 7.46 (d, J=8 Hz, 1H), 7.53 (d, J=8.8 Hz, 2H), 7.75 (t, J=8 Hz, 1H), 8.30 (s, 1H), 9.30 (s, 1H), 9.95 (s, 1H); LCMS: m/e 496 (M+1).

Workup

  1. waitat rt for 2 h
  2. customat 0° C.
  3. stirringto stir at 0° C. for 1 h
  4. washwashed with 10% NaHCO3 (2 mL), water (2 mL) and brine (2 mL)
  5. dry with materialdrying over Na2SO4
  6. concentrationfollowed by concentration under reduced pressure
  7. customgave a residue which
  8. customwas further purified by column chromatography (SiO2, 60-120, chloroform/methanol, 9/1)

Sources & evidence

ORD record
ord-0696727ebdba4bfdbbc82598d988c39c
Source dataset
uspto-grants-2014_06
Patent number
US08748606B2

Reaction notes

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